Pulmonary alveolar proteinosis (PAP) is a recently recognized chronic disease of the lungs with characteristic deposition of a PAS- positive granular and floccular proteinacious material in the alveoli. Affected patients suffer from inadequate gas exchange, and many of them die with complications of bacterial and fungal infections. The pathogenesis of this striking disease is unknown. No specific therapy nor specific preventive measures are available. A review of the literature as well as our experience with PAP indicates that this is most likely caused by some post-natal factor. This could be either infection or an abnormal host response, to some foreign substance. We propose to search for an abnormal host response, using modern immunologic methodology. The idea that an abnormal host response might be a major factor in the pathogenesis is supported by two pieces of evidence; (1) About 1/3 of 23 children with PAP were reported to have thymic alymphoplasia, a condition in which there is clearly abnormal immune function, (2) we found a relative accumulation of IgG and IgA and sometimes of IgE in the bronchial fluids of PAP patients who superficially appeared to be immunologically intact. A specific defect in one aspect of immune defense and/or an over-reactivity of another aspect could be at fault. Also experimental studies with rats have shown that quartz inhalation can result in either silicosis or pulmonary alveolar proteinosis similar to human PAP. This suggests that inhalation of particles may result in PAP, in animals which are possibly immunologically inadequate. We will attack the question by three approaches: (1) cellular immune response, (2) phagocytic response, (3) humoral, especially IgG, IgA and IgE antibody responses. Our long term goal is to discover means of specific therapy and prevention of PAP.